Administration of therapeutic agents to the mucosa is well known in the art. Therapeutic agents can be delivered to the nasal cavity, the vaginal cavity, pulmonarily, buccally, sublingually, rectally, orally and to the eye for the local treatment of diseases or for a systemic effect.
Delivery of drugs via the absorptive mucosa, eg the buccal, nasal, ocular, oral, sublingual, rectal, and vaginal mucosae, offers distinct advantages over other routes of administration. In particular, these body cavities are easily accessible, so administration is convenient. Therapeutic agents administered via a mucosal route, except via the gastrointestinal tract, are transported directly into the systemic circulation and therefore avoid first-pass metabolism. Mucosal routes of delivery also provide the potential for a rapid pharmacological response, especially the nasal and pulmonary routes of delivery. Lipophilic drugs such as propranolol and fentanyl are readily absorbed through the nasal mucosa, resulting in a high bioavailability.
Additionally, drugs can be absorbed directly into the CNS after nasal administration by crossing the olfactory mucosa or being transported via the trigeminal nerve system in the nasal cavity.
Despite the advantages of mucosal routes of delivery, many therapeutic agents, such as peptides and proteins and hydrophilic small molecular weight drugs, are poorly absorbed across a mucosal membrane due to their physicochemical characteristics (eg large molecular weight, hydophilicity, lability), and must therefore be administered by injection or infusion. For some of these drugs, such as insulin administered to type 1 diabetics, a multiple daily dosing by injection is necessary and results in non-compliance, especially among younger patients (Drug Discovery Today, 7, 2002, 1184-1189; J Control Rel, 87, 2003, 187-198). In particular, agents of large molecular weight and/or high hydrophilicity are poorly absorbed across mucosal membranes.
The mucosal membranes provide a protective barrier against the outside environment and are lined by epithelial cells which provide a barrier to the entry of toxins, bacteria and viruses. Pathways involved with transport of therapeutic agents across mucosal membranes include transcellular and paracellular transport. In the transcellular route, therapeutic agents may be transported by a passive or carrier-mediated transport system. The passive, transcellular route involves permeation across the apical cell membrane, the intracellular space and basolateral membrane and is limited to relatively small hydrophobic compounds. Larger compounds may be absorbed by endocytosis, but this mechanism is selective, eg to particular classes of molecule and structural analogues of naturally transported analogues, and generally excludes compounds of a highly polar nature. Paracellular transport allows larger more hydrophilic therapeutic agents across mucosal membranes by passive diffusion across the intercellular junctions of the epithelium. Paracellular transport of therapeutic agents is therefore restricted by the tight epithelial junctions.
Thus, agents that are poorly absorbed across the mucosal membranes may include small molecules that are hydrophilic. Examples include morphine and other similar opioids. More commonly, they are large, high molecular weight molecules and transport is inhibited on account of their size and their hydrophilicity. This is a particular problem for biologic drugs or “biologics”, such as peptides and proteins, polynucleic acids, SiRNA, RNA and antigens, since these are mostly large molecular weight molecules of a polar nature. This problem is exacerbated by the discovery of increasing numbers of biologics due to growth in biotechnology research and scientific advances.
A further problem regarding the delivery of biologics, is that biologics are prone to degradation by enzymes such as peptidases and proteases, especially when administered via the gastrointestinal tract. Delivery through a mucosal membrane such as that found lining the nasal cavity would provide an important alternative route of delivery with limited enzymatic degradation.
In order to improve the transport of these drugs across mucosal surfaces formulations that include absorption enhancers have been employed with some success, especially when delivered by nasal administration. Absorption agents used to date include surfactants, gelling microspheres and the bioadhesive polymer, chitosan. Examples of these systems have been reviewed by Illum and Fisher in “Inhalation Delivery of Therapeutic Peptides and Proteins”, Adjei and Gupta (eds.) Marcel Dekker Inc, New York (1997), 135-184 and by Costantino, Illum, Brandt, Johnson and Quay, Intranasal delivery: Physicochemical and Therapeutic Aspects, Int J Pharm, 337, 2007, 1-24.
However, absorption enhancers employed previously in nasal studies, such as salicylates, bile salts and bile salt derivatives, phospholipids and lysophospholipids, sodium lauryl sulphate and cyclodextrins and chitosan derivatives, have in some cases been shown to result in irritation or damage to the mucosal membrane.
A variety of other mucosal absorption enhancer systems have been developed to deliver therapeutic agents across a mucosal membrane, but problems reported have included irritation, malabsorption and clearance of the therapeutic agent preventing successful absorption into the systemic circulation. Many excipients such as polyethylene glycol and glycofurolum (U.S. Pat. No. 5,397,771) can be highly viscous and therefore unsuitable for intranasal and mucosal delivery.
WO 03/070280 describes the use of mono- and diglycerides having the formula

wherein R1, R2 and R3 are selected from the group consisting of from C6-C26 fatty acids, PEG polymers and hydrogen, provided that at least one of R1, R2 and R3 is a C6-C26 fatty acid residue and at least one of R1, R2 and R2 is a PEG polymer residue, for use as absorption enhancing and as mucoadhesive agents.
WO 2004/064757 describes the use of N,N-dimethylglycine, thioctic acid, sebacic acid and shikimic acid and salts thereof for enhancing the absorption of a pharmaceutically active agent through mucosal membranes.
WO 2006/097793 describes compositions for translocating therapeutically active molecules through biological membranes by including molecules in a water-soluble composition. The water-soluble composition can be immersed in a hydrophobic medium. The hydrophobic medium can consist of aliphatic, cyclic, or aromatic molecules. Examples of suitable aliphatic hydrophobic medium include mineral oil, monoglycerides, diglycerides, triglycerides, ethers and esters. Examples of suitable cyclic hydrophobic medium include terpenoids, cholesterol, cholesterol derivatives and cholesterol esters. Examples of aromatic hydrophobic medium include benzyl benzoate. The composition is further supplemented by membrane fluidizing agent which can be linear, branched, cyclical or aromatic alcohols.
WO 03/099264 describes compositions for vaginal, buccal or nasal delivery of drugs and cryoprotection of cells and embryos. The compositions consist of a non-ionizable glycol derivative in combination with a pharmaceutically active agent. The non-ionizable glycol derivative may be further combined with a mucoadhesive agent and a lipophilic or hydrophobic carrier for adhesion to, and transport through, a mucosa. A non-ionizable glycol derivative is a conjugate of aliphatic glycol or a conjugate of aliphatic glycol with aliphatic or aromatic alcohol or esters. The non-ionizable glycol derivative is selected from the group consisting of a glycol ester, glycol ether, a mixture of glycerol esters or a combination thereof.
WO2005/046671 is concerned with the formation of submicron particles of paclitaxel or its derivatives by precipitating the paclitaxel in an aqueous medium to form a pre-suspension followed by homogenisation. The particles produced generally have an average particle size of less than about 1000 nm and are not rapidly soluble. Surfactants with phospholipids conjugated with a water soluble or hydrophilic polymer are used to coat the particles. Solutol® HS15 is given as an example of a suitable surfactant, and in Example 5 it is stated that “The stabilisation that occurs as a result of homogenisation is believed to arise from rearrangement of surfactant on the surface of the particle. This rearrangement should result in a lower propensity for particle aggregation (page 31, lines 29-32)”. Thus, surfactant is used to stabilise the particles and prevent agglomeration. The described particles are purported to show improved bioavailability because of increased dissolution due to their small size.
WO2006/108556 refers to the use of an admixture of surfactant and phospholipid to solubilise poorly soluble active agents, eg corticosteroids, in colloidal form. Macrogol hydroxystearate (Solutol® HS15) is one of the exemplified surfactants. The improved solubility of the active agent enables improved delivery of that agent to the intended site. For example, the formation of colloidal solutions improves delivery by nebuliser (advantages discussed on page 46 line 8-page 47, line 22).
WO99/32089 relates to a pharmaceutical composition comprising micelles in an aqueous medium, wherein the micelles comprise a lipophilic glucocortocosteriod and one and only one pharmaceutically acceptable surfactant. The surfactant is used in low concentrations of less than 5% w/w of the total composition weight (page 7, lines 1-2) in order to form micelles. A preferred surfactant is polyoxyethyleneglycol 660 12-hydroxy stearate (Solutol® HS15).
US2007/259009 refers to an aqueous pharmaceutical preparation for administration of a lightly soluble PDE4 inhibitor. Alkoxylated fats are used as cosolvent in order to obtain clear solutions having the properties necessary for parenteral preparations (paragraph [0006]). A preferred example of a suitable alkoxylated fat is Solutol® HS15 (paragraph [0016]).
WO2005/105050 and US2006/088592 describe a composition for oral delivery of a poorly absorbed drug. The composition includes the drug, an enhancer for increasing absorption of the drug through the intestinal mucosa, and a promoter, which alone does not increase the absorption of the drug, but which further increases the absorption of the drug in the presence of the enhancer. In Example 12, paclitaxel is solubilised using Solutol® or tocopheryl succinate polyethylene glycol as solubiliser. The enhancer and promoter used in Example 12 are sucrose stearate and glucosamine, respectively.
US2007/082016 relates to pharmaceutical compositions in the form of a microemulsion preconcentrate comprising a δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide renin inhibitor in an absorption enhancing carrier medium comprising (a) a lipophilic component; (b) a high HLB surfactant; and (c) a hydrophilic component. The preconcentrate provides a spontaneously dispersible water-in-oil microemulsion which upon further dilution in aqueous medium, eg gastric fluids, converts to oil-in-water microemulsion. Suitable high HLB surfactants include, but are not limited to, non-ionic efflux inhibiting and thereby absorption enhancing surfactants (paragraph [0037]). Solutol® HS15 is listed as a suitable efflux inhibitor (paragraph [0038]).
WO01/19335 is concerned with vaccine compositions in which the antigen is encapsulated in vesicles allowing delivery of the antigen through mucous membranes. The vesicles are multilamellar vesicles with an onion-like structure having an internal liquid crystal structure formed by a stack of concentric bilayers based on amphiphilic agents alternating with layers of water, an aqueous solution or a solution of a polar liquid and into which at least one antigen is incorporated. The vesicles may be formed by a wide variety of surfactants, polyethylene glycol hydroxystearate being mentioned. Preferably the compositions involve a mixture of different surfactants.
WO00/00181 relates to pulmonary drug delivery compositions useful for the inhaled delivery of corticosteroid compounds. A high HLB surfactant, preferably an ethoxylated derivative of vitamin E and/or a polyethylene glycol fatty acid ester such as Solutol® HS15 is used to solubilise the corticosteroid in order that it may be delivered by nebulisation or nasal delivery.
US2005/058702 describes an approach to facilitating the translocation across biological barriers of negatively charged molecules that are themselves unable to cross such barriers (which molecules are referred to as “effectors”). The approach involves formulating the effector with an ionic liquid forming cation. It is disclosed that the formulation may also contain a mixture of at least two substances selected from the group consisting of a non-ionic detergent, an ionic detergent, a protease inhibitor, and a reducing agent. The Examples disclosed include several such substances, including Solutol® HS15, though the concentrations of that ingredient and others are not specified. The Example formulations are said to be administered rectally or by injection into an intestinal loop.
WO 2006/024138 describes a pharmaceutical formulation having thermoreversible properties, comprising (a) an antimicrobial agent, (b) a poloxamer mixture containing at least two poloxamer polymers, and (c) a hydroxyl fatty acid ester of polyethylene glycol, wherein the formulation is solid at room temperature and is a liquid-gel at body temperature. In preferred embodiments, the hydroxy fatty acid ester of polyethylene glycol is polyethylene glycol 660 hydroxystearate. The formulation is for use in a suppository form, for administration and delivery of active pharmacological agents via the vaginal or rectal routes.
Buggins et al, “The effects of pharmaceutical excipients on drug disposition”, Advanced Drug Delivery Reviews 59 (2007) 1482-1503, is a literature review describing the reported effects of commonly used co-solvents and excipients on drug pharmacokinetics and on physiological systems which are likely to influence drug disposition. The effects of Solutol® on oral absorption are discussed in part 4.3.4 on page 1497. Solutol® has been shown to increase oral absorption of the poorly soluble drug cyclosporin A. This effect was thought to be predominantly due to increased solubility of the cyclosporin in the intestinal fluid, although inhibition of CYP3A (a member of the CYP450 family of enzymes) and P-Gp may have played a part (Bravo Gonzalez et al, Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol® HS15 containing self-dispersing formulation and a microsuspension, Int. J. Pharm. 245 (2002) 143-151).
The paper describes how the effects of Solutol® on the oral absorption of the water-soluble drug colchicines have also been investigated. The high solubility of colchicines means that the increase in oral absorption is unlikely to be due to increased drug solubility in the intestinal fluids due to Solutol. Inhibition of P-Gp and/or CYP450 are suggested as possible mechanisms; the authors concluded that CYP450 inhibition is likely to be the major mechanism of enhanced absorption in this case, as CYP450 concentrations are high and P-Gp concentrations are low (Bittner et al, Improvement of the bioavailability of colchicine in rats by co-administration of D-alpha-tocopherol polyethylene glycol 1000 succinate and a polyethoxylated derivative of 12-hydroxy-stearic acid, Arzneim-Forsch, 52 (2002) 684-688).
It is also reported that Solutol® HS15 significantly increased digoxin transport across an everted rat gut sac in vitro, an effect attributed to the inhibition of drug efflux by P-Gp transporters (Cornaire et al, Impact of excipients on the absorption of P-glycoprotein substrates in vitro and in vivo, Int. J. Pharm. 278 (2004) 119-131).
Thus, the prior art contains numerous disclosures of the use of polyethylene glycol esters of hydroxystearic acid in pharmaceutical compositions. Such uses have, however, been restricted to the solubilisation of poorly soluble drugs and/or inhibition of P-Gp and CYP450. Indeed, Solutol® HS15 is marketed as a non-ionic solubilizer for injection solutions. The ability of such materials to enhance absorption of drugs across mucosal membranes, including hydrophilic drugs (for which solubilisation is not an issue) and/or large molecule drugs such as many biologics, has hitherto not been recognized.
There remains an urgent need for the development of efficient, non-toxic absorption enhancer systems that will enable a therapeutically relevant transport of high molecular weight and/or hydrophilic compounds across mucosal surfaces.
Transdermal drug delivery—the delivery of drugs across the skin and into systemic circulation—may also be an advantageous route of drug delivery, particularly because of the relative accessibility of the skin. However, transdermal delivery is also hampered by the problems mentioned above for drug delivery across mucosal membranes. The skin's low permeability limits the number of drugs that can be delivered in this manner, with the result that many hydrophilic compounds and/or compounds of high molecular weight are not currently deliverable by the transdermal route. Without the use of absorption enhancers, many drugs will not diffuse into the skin at a sufficient rate to obtain therapeutic concentrations. A particular concern for transdermal delivery is the possibility that a local irritation will develop at the site of application. There remains a need for the development of efficient, non-toxic absorption enhancer systems for enhancing the transport of high molecular weight and/or hydrophilic drug compounds.
We have now discovered that fatty acid esters of polyethylene glycol are able to enhance considerably the transport of a wide range of therapeutic agents across mucosal surfaces or the skin without causing irritation and without creating any damage, and thus constitute a novel group of absorption enhancers.
As noted above, hydroxy fatty acid esters of polyethylene glycol are known for their use as solubilising agents. In particular, polyethylene glycol 660 hydroxy fatty acid ester (macrogol 15 hydroxystearate) is marketed as a non-ionic solubilizer for injection solutions.